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Instrumental variable analysis can estimate treatment effects in the presence of residual or unmeasured confounding. We compared ordinary least squares regression versus instrumental variable estimates of the effects of selective cyclooxygenase-2 inhibitors (COX-2s) relative to nonselective nonsteroidal anti-inflammatory drug (NSAID) prescriptions on incidence of upper gastrointestinal complications and myocardial infarction (MI).We sampled a cohort of 62,933 first-time users of COX-2s or nonselective NSAIDs older than 60 years in the Clinical Practice Research Datalink. The instruments were physicians’ previous prescriptions of COX-2s or nonselective NSAIDs, which are surrogates for physician preferences. We estimated risk differences of incident upper gastrointestinal complications and MI within 180 days of first COX-2 versus nonselective NSAID prescription.Using ordinary least squares regression, adjusted for baseline confounders, we observed little association of COX-2 prescriptions with incident upper gastrointestinal complications (risk difference = −0.08 [95% confidence interval = −0.20 to 0.04]) or MI (0.06 [−0.06 to 0.17]) per 100 patients treated. Our adjusted instrumental variable results suggested 0.46 per 100 (−0.15 to 1.07) fewer upper gastrointestinal complications and little difference in acute MIs (0.08 per 100 [−0.61 to 0.76]), within 180 days of being prescribed COX-2s. Estimates were more precise when we used 20 previous prescriptions; the instrumental variable analysis implied 0.74 (0.28 to 1.19) fewer MIs per 100 patients prescribed COX-2s.Using instrumental variable analysis, we found some evidence that COX-2 prescriptions reduced the risk of upper gastrointestinal complications, consistent with randomized controlled trials. Our results using multiple instruments suggest that COX-2s may have heterogeneous within-class effects on MI.